The overall objective of the proposed studies is to develop mathematical pharmacodynamic models to assist in the development and clinical use of anticancer drugs. The initial screening for anticancer drugs and drug combinations is done primarily in vitro. In Specific Aim 1, in vitro data will be used to develop improved models to describe dependence of cell kill on time-course of cellular drug exposure for about 25 anti-cancer drugs either in current clinical use or in development. The models will be based on a consideration of drug transport processes and binding at the cellular level. For the design of preliminary clinical trials, and for optimization of dosing and scheduling, a key question is how in vitro data can be used to predict in vivo response. In Specific Aim 2, this issue will be addressed, by incorporating the cellular-level models from Aim 1 into models for uptake of drug by tumors, taking into account plasma pharmacokinetics, tumor microvasculature, and drug transport from microvessels into tissue. These models will be used to predict the spatial distribution of cell kill in vivo. A large fraction of chemotherapy regimens now involve drug combinations, and there are ongoing screening efforts to identify promising new combinations. Generally, these tests for drug synergy are also initially done in vitro. In Specific Aim 3, models developed for two or more individual drugs, from Aims 1 and 2, will be combined to obtain better criteria for drug synergy in vitro, and a better understanding of what drug properties found in in vitro studies can be expected to lead to successful combination therapy. The proposed models will be developed in collaboration with experimental researchers and clinicians.